Anti-inflammatory agents

ABSTRACT

Methods of treating various conditions involving inflammation and its concomitant swelling, tenderness, decreased mobility, pain, and fever, employing an aralkyl hydrocarbon as the active anti-inflammatory agent.

i United States Patent m] Marshall 5] Dec. 31, 1974 I ANTl-INFLAMMATORY AGENTS [58] Field of Search....'. 424/340 [75] Inventor: Winston S. MarshalL'Indianapolis,

, Ind. [56] References Cited [73] Assignee: Eli Lilly and Company, Indianapolis, OTHER PUBLICATIONS Ind. Chem. Abst., Vol. 66 (1967), 46668Q.

22 F1 1 Y Y 1 led Oct 1972 Primary Examiner-Stanley J. Friedman [2 APP N05 301,685 Attorney, Agent, 0r Firm-KathleenS. Page; Everet F.

I Related US. Application Data Smlth [60]- Division of Ser; No. l29,237, March 29, 1971, Pat.

No. 3,745,223, which is a continuation-in-part of Ser. [57] I ABSTRACT I No. 91,569, Nov. 20, 1970, abandoned, Which is 8 Methods of treating various conditions involving inm -P of 888,802 flammation and its concomitant swelling, tenderness, 1969 abandoned decreased mobility, pain, and fever, employing an lk l h Cl b th I t ii I 52 US. Cl 424/340, 424/263, 424/275, zg y mar on as 6 ac we an 1 m amma my I 424/337 [51 13 Claims, No Drawings Int. Cl A6lk 27/00 1 ANTI-INFLAMMATORY AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS Thisis a division of copending application Ser. No. 129,237, filed Mar. 29, 1971 and issued July 10, 1973 as US. Pat. No. 3,745,223. Application Ser. No. 129,237 was, in turn, a continuation-in-part of then pending application Ser. No. 91,559, filed Nov. 20, 1970 and abandoned after the filing of application Ser. No. 129,237. Application Ser. No, 9 l ,559 was, in turn, a continuation-'in-part of then pending application Ser. No. 888,802, filed .Dec. 29, 1969 and abandoned after the filing of application Ser. No. 91,559.

BACKGROUND OF THE INVENTION Mammals, both humans and animals, are known to suffer from various conditions involving inflammation and its concomitant swelling, tenderness, decreased mobility, pain, and fever. While there are a number of anti-inflammatory agents which are effective in the symptomatic treatment of inflammatory conditions such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, degenerative joint diseases, and the like, such agents have been found to have a number of undesirable side effects, among them gastric irritation. Thus, the search for improved anti-inflammatory agents continues.

The present invention provides a method of treating inflammation in humans and animals byemploying an appropriate aralkyl hydrocarbon as the antiinflammatory agent. The compounds employed in 'the practice of this invention appear to be relatively free from the serious gastric side effects produced by a number of commerically available anti-inflammatory agents. 7

' SUMMARY OF THE lNVENTlON' This invention relates to a method of treating inflammation and the resulting pain and fever in mammals, both humans and animals. More particularly, this in vention provides a method of treating inflammatory disorders which comprises administering to a subject suffering from such condition from 1 to 100 mg./kg. of body weight daily of an aralkyl compound represented by the formula wherein:

Ar represents an aryl moiety selected from the'group consisting of 3-phenoxyphenyl, 4-phenoxyphenyl, 3- phenylthiophenyl, 4-phenylthiophenyl, 4- cyclohexylphenyl, 4-( l -cyclohexenyl)phenyl, 4- biphenylyl, 4-iso-butylph enyl, 4-cyclohexyl-3- chlorophenyl, 3-methyl-4-phenoxyphenyl, or 3-methoxy-4-phenoxyphenyl, 4-iso-propylphenyl, 4-( lcyclooctenyl)phenyl, 4-cyclooctylphenyl, 4'- fluorobiphenylyl, 4-tert-butylphenyl, 6-methoxy-2- naphthyl, 4-(2-norbornyl)-phenyl,- S-indanyl, 3-chloro- 4-allyloxyphenyl, 4-'n-propylphenyl, 4-n-butylphenyl, 4-sec-butylphenyl, 4-cyclopentylphenyl, 4-neopentylphenyl, Z-phenyI-S-pyridyl, 4-(2'- pyridyl)phenyl, 4-cyclobutylphenyl, and -phenyl-2- thienyl; and

R represents iso-propyl, iso-propenyl, iso-butyl, or n-butyl, with the limitations that when R is n-butyl, Ar

-tory conditions in mammals.

DETAILED DESCRIPTION OF THE INVENTION According-to the method of this invention, symptomatic reliefof inflammation and the accompanying swelling, tenderness, decreased mobility, pain and fever is provided when from 1 to I00 mg./kg. ofbody weight daily of an aralkyl compound, as defined herein, is administered to humans and animals suffering from an inflammatory condition by either oral or parenteral routes.

The aralkyl hydrocarbons useful in the practice of this invention are represented by the formula ArR wherein:

Ar represents an aryl moiety selected from the group consisting of 3-phenoxyphenyl, 4 -phenoxyphenyl, 3- phenylthiophenyl, 4-phenylthiophenyl, 4- cyclohexylphenyl, 4-( l-cyclohexenyl)phenyl, 4- biphenylyl, -4-iso-butylphenyl, 4-cyclohexyl-3- chlorophenyl, 13-methyl-4-phenoxyphenyl, or

- 3-methoxy-4-phenoxyphenyl, 4-iso-propylphenyl, 4-(

cyclooctenyl)phenyl, 4-cyclooctylphenyl, 4- fluorobiphenylyl, 4-tert-butylphenyl, 6-methoxy-2- naphthyl, 4-(2-norbornyl)phenyl, S-indanyl, 3-ch1oro- 4-allyloxyphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-sec-butylphenyl, 4-cyclopentylphenyl, 4-neopentylphenyl, 2 phenyl-5-pyridyl, 4-(2-pyridyl)- phenyl, and I R represents iso-propyl, iso-propenyl, n-butyl, or isobutyl, with the limitations that when R is n-butyl, Ar is 4-biphenylyl, and when R is iso-butyl, Ar is 4- phenoxyphenyl.

Included among the compounds useful in the practice ofthis invention are 3-phenoxy-a-methylstyrene S-phenoxycumene 4-phenoxy-a-methylstyrene 4-ph'enoxycumene 4-iso-butyldiphenyl ether 4-n-butylbiphenyl 4-phenylcumene 4-iso-butyl-oz-methylstyrene 4-iso-butylcumene 3-phenylthio-a-methylstyrene 4-phenylthio-a-methylstyrene 4-cyclohexyl-a-methylstyrene 4-cyclohexylcumene 3-chloro-4-cyclohexyl-a-methylstyrene 3-methyl-4-phenoxy-a-methylstyrene 3-methoxy-4-phenoxycumene 4-iso-propyl-a-methylstyrene 4-iso-propylcumene 4-n-propylcumene 4-cyclobutylphenyl, and 5-phenyl-2-thienyl;

4-n-butyl-a-methylstyrenc 4-sec-butyl-a-methylstyrene l-(4 cumenyl)cyclooctene 4-cyclooctylcumene 4-(4-flurophenyl)-a-methylstyrene 4-(3-fluorophenyl)-a-methylstyrene 4-(4-fluorophenyl)cumene 4-(3-fluorophenyl)cumene 3-methoxy-4-phenoxy-a-methylstyrene 2-iso-propenyl-6-methoxynaphthalene 4-tert-butyl-a-methylstyrene 4-(2-norbornyl)cumene S-iso-propenylindane 3-chloro-4-alyloxy-a-methylstyrene 4-cyclopentylcumene 4-(1-cyclohexenyl)cumene 4-neo-pentylcumene 2-phenyl-5-isopropenylpyridine 2-phenyl-5-isopropylpyridine 4-cyclohutylcumene 4phenyl-a-methylstyrene 4-cyclobutyl-a-styrene 4-(2-pyridyl)cumene Z-isopropyl-S-phcnylthiophene The compounds employed in the practice of this invention are excellent anti-inflammatory agents and are generally free from the usual gastric side effects seen with other such agents. Examples of such antiinflammatory activities are given in the table which follows. The oral ED50s, expressed in mg./kg., of the compounds employed in this invention, as determined in the erythema blocking assay carried out essentially according to the method reported by Winder, C.V. et

al., Archives Int. Phurmacadym, Vol. 116, p. 261 (1958), are shown in the following table.

TABLE I Oral Ar R ED (mg/kg.)

3-Phenoxphenyl iso-propenyl 5 3-Phenoxyphenyi isc-propyl 25 4-Phcnoxyphenyl iso-propenyl l5 4-Phenoxyphcnyl iso-propyl 6 4-Phcnoxyphenyl iso-butyl 20 4-Biphenylyl n-hutyl I 4-Biphenylyl iso-propyl 4 4-iso-Butylphenyl iso-propenyl 40 4-iso-Bulylphenyl iso-propyl 8 3-Phcnylthiophenyl isopropenyl 50 4-Phenylthiophenyl iso-propcnyl 30 4-Cyclohexlphenyl iso-propenyl 35 4-Cyclohexylphenyl isopropyl l 4-( I-Cyclohexenyl)phenyl isopropyl 50 3-Methyl-4-phenoxyphenyl iso-propenyl 50 3-Methoxy-4-phenoxyphenyl iso-propyl l5 4-n-Propylphenyl iso-propyl 50 4-iso-Propylphenyl iso-propenyl 25 4-iso-Propylphenyl iso-propyl 0.8 4-( l-CyclooctenyUphcnyl iso-propyl 25 4-Cyelooctylphenyl iso-propyl 5 4'-Fluorobiphenylyl iso-propenyl 23 4-Fluorobiphenylyl iso-propyl 50 3-Methoxy-4-phenoxyphenyl iso-propenyl 22 6-Methoxy-2-naphthyl iso-propenyl 25 3-Chloro-4-allyloxyphenyl iso-propenyl 50 4'n-Butylphenyl iso-propenyl 50 4-see-Butylphenyl iso-propenyl 25 4-Cyelopentylphenyl iso-propyl 50 J-neo-Pentylphcnyl iso-propyl 25 4-tcrl-liutylphenyl iso-propenyl 44'l-Nnrhornyl)phenyl isn-propyl I00 S-lnl 1 50 iso-propenyl Generally speaking, the compounds employed in the practice of this invention are prepared by methods well known in the art for the preparation of aralkyl hydrocarbons. The compounds employed herein can be prepared from an appropriate arylcarboxylic acid or acctophenone according to the following reaction schemes. Hereinbelow Ar is an aryl moiety as defined in the generic formula and R represents lower alkyl.

( R on Ar-COOII Ar-COOR- ClIgMgx G) EHO OH CH3 Hz/Pd Ar-C-CHa Ar-CH EtOAe CH;

H2SO4 (4N) Hz/Pt Ar(I1=CHz CH 11) o OH CH;

(Grignard) ([1 Hz/Pd Ar-C Ar- CH r-OH HaMgC I EtOAe CH3 CH3 CH OaP CH3X -Ar-C Ar-C=CH2 NaH CH3 Wittig CH3 ll Hz/Pd Ar-CCH2CH2CH3 Ar-CI-IzCHzCHzCH;

EtOAC,H

HzN-NH:

Another aspect of this invention contemplates and provides a pharmaceutical preparation in dosage unit form adapted for administration to obtain an antiinflammatory effect comprising per dosage unit, an anti-inflammatory effective, nontoxic amount within the range from about 50 to about l,000 milligrams of at least one compound of the formula Ar-R as defined herein above, and a pharmaceutical diluent. A preferred'pharmaceutical formulation is one adapted for oral administration and would include the administration of the compound in soft gelatin capsules, hard gelatin capsules, and tablet formulations illustrated below. A preferred compound for administration in accordance with this aspect of the invention is 4- phenylcumene, but other compounds listed above can be substituted for part or all of the 4-phenylcumene.

The above compounds can be prepared by methods well known in the art. The following examples illustrate methods which can be employed in preparing the compounds useful in the practice of this invention.

EXAMPLE 1 Preparation of 2-(4-biphenylyl)-2-propanol A solution of 98 g. of 4-acetylbiph enyl, dissolved in 500 ml. of ether and 500 ml. benzene, was added dropwisc, with stirring, to 500 ml. of a.2.15 molar solution of methyl magnesium chloride which had been diluted with an equal volume of ether, at such'a rate that the reaction refluxed gently. After the addition was completed, the reaction wa refluxed gently overnight.

The reaction was then allowed to cool to room temperature, and the excess Grignard reagent was decomposed by the dropwise addition of 178 ml. of a saturated ammonium chloride solution. The organic layerwas decanted from the resulting inorganic residue and poured into ice water. The organic layer wash then separated, washed with dilute sodium bicarbonate solution and water, and dried over sodium sulfate. Evaporation ofthe solvents in vacuo left a white solid residue which was crystallized from hexane to yield 85 g. of 2-(4- biphenylyD-Z-propanol, m.p., 88.5-90.5C.

Analysis. Calc. for C H O: C. 84.87; H. 7.60. Found: C. 85.01; H. 7.54.

This compound can be used to prepare 4-phenyl-amethylstyrene by the method of Example 13.

EXAMPLES 2-12 The following compounds were prepared according to the method of Example 1, from the corresponding acetophenone or substituted benzoate ester, using appropriate amounts of methyl magnesium halide solut1on:

phenylthioacetophenone Analysis. Calc. for C H OS: C. 73.72; H. 6.60; S. 13.12. Found: C. 73.46; H. 6.63; 5. 13.35.

6 2-(4-Phenylthiophenyl)-2-propanol, b.p., l44153C./0.09 mm.; 11 1.6154, from 4- phenylthioacetophenone.

Analysis. Calc. for C, -.H, OS: C. 73.72; H. 6.60; S. 13.12. Found: C. 73.99; H. 6.89; S. 1291.

2-(4-iso-Butylphenyl)-2-propano1, b.p., 77-85/0.16 mm.; n 1.5050, from 4-iso-butylacetophenone.

Analysis. Calc. for C H O: C. 81.20; H. 10.48. Found: C. 80.97; H. 10.52.

2-(4-sec-Butylphenyl)-2-propano1, 73-80/0.05 mm.; n 1.5094. butylacetophenone.

b.p., from 4-sec- Analysis. Calc. for C H- O: C. 81.20; H. 10.48. Found: C. 81.09;H. 10.71.

2-(4-Cycl0hexy1pheny1)-2-propanol, 71-74C., from 4-cyclohexylacetophenone.

Analysis. Calc. for CISHHOZ C. 82.51; H..10.16. FoundrC. 82.49; H. 10.04.

2-(3-Methoxy-4-phenoxyphenyl)-2-propanol, b.p., 170177/0.07 mm. 1.5762, from 3-Methoxy-4- phenoxyacetophenone. I

Analysis. Calc. for C H Q z C. 74.39; H. 7.02. Found: C. 74.58; H. 7.29.

2-(3-Methyl-4-phenoxyphenyl)-2-propano1, 145146/0.08 mm., m, 1.5705, from. 3-Methyl-4- phenoxyacetophenone.

Analysis. Calc. for C H O z C. 79.31; H. 7.49. Found: C. 79.47; H. 7.63.

2-(4-tert-butylphenyl)-2-propano1, m.p., 76.5. from ethyl 4-tert-Butylbenzoate.

Ana1ysis.Ca1c. for c..H..,o;-c. 81.20; H. 10148 Found: c. 80.98; H. 10.58

2-(4'-fluorobiphenylyl)-2-propano1. m.p., l 10-111, from 4'-f1uoro-4-acety1bipheny1.

Analysis, Calc. for c,,H,,1=o;c. 78.24; H. 6.57. Found: C, 77.95; H, 6.79.

2-( 6-methoxy-2-naphthy1)-2-propanol, 8 3-8 6, from 2-acetyl-6-methoxynaphthalene.

Ana1ys'is,Culc. for CHHKOZ: c, 77.75; H, 7.46; 0, 14.79. Found-2 C, 77.54; H, 7.22; 0, 14.96.

These alcohols are converted to the a-methylstyrenes by the acid method exemplified in Example 13.

EXAMPLE 13 Preparation of 4-pheny1-a-methylstyrene A suspension of 42.4 g. of 2-(4-biphenylyl)-2- propanol in 100 ml. of 4N sulfuric acid and 50 ml. of ethanol was refluxed and stirred vigorously for 1.5 hours. Then 50 ml. of ethanol was added, and the reaction was refluxed with stirring foor an additional 2.5 hours. After being cooled to room temperature, the reaction mixture was poured into ice water and extracted with ether, benzene, and chloroform. The organic extracts were combined, washed with sodium bicarbonate solution and water, and dried over sodium sulfate. After evaporation of the solvents in vacuo, the residue was crystallized from hexane to yield 23.4 g. of I 4-phenyl-oz-methylstyrene, m.p., 116118C.

Analysis, Calc. for C, .,H C, 92.74; H, 7.26. Found: C, 92.45; H, 6.98.

EXAMPLES l426 the following compounds were prepared according to the method of Example 13, using the corresponding propanol as the starting material:

4-Phenoxy-a-methylstyrene, b.p., 120-126/0.08 mm.; 17 1.5934, from 2-(4-phenoxyphenyl)-2- propanol.

Analysis, Calc. for c. .,H,.o; c, 85.68; H. 6.71. Found: c, 85.44; H. 6.87.

3-Phenylth'io-a-methylstyrene, b.p.,. ll31l5/0.05 mm.; n 1.6248 which contained 10 percent starting carbinol as measured by Nmr from 2-(3-phenylthiopheny1)-2-propanol.

4-Phenylthio-a-methylstyrene, b.p., l47l67/0.2 mm.; 11,, 1.6374, from 2-(4-phenylthiophenyl)-2- propanol.

4-iso-Butyl-a-methylstyrene, b.p., '100/0.4 mm.; m, 1.5182, from 2-(4-iso-butylpheny1)-2-propano1.

Analysis, Calc. for C H C, 89.59; H, 10.41. Found: (189.52; H. 10.49.

4-sec-Butyl-a-methylstyrene, b.p., 52-53/0.07 mm.; m, 1.5188, from 2-(4-sec-buty1phenyl)-2-propano1.

Analysis, Calc. for C H C, 89.59; H, 10.41. Found: C, 89.36; H. 10.43.

4-Cyclohexyl-a-methylstyrene, b.p., 122142/0.15 mm.; n 1.5484,'from 2-(4-cyclohexylphenyl)-2- propanol.

Analysis, Calc. for C H C. 89.94; H. 10.06. Found: C. 90.15; H. 10.33.

4-(1-Cyc1ohexeny1)cumene, b.p., 148160/5 mm.; n 1.5452, from 1-(4-cumenyl)-l-cyclohexanol.

71 1.5184, from 2-(4-tert-butylphenyl)-2-propano1.

Analysis, Calc. for C H C. 89.59; H, 10.41. Found: C, 89.33; H, 10.20.

3-Methy1-4-phenoxy-a-methylstyrene, 125-134/0.008 mm.; n 1.5856, from methyl-4-phenoxyphenyl)-2-propanol.

Analysis, Calc. for C H S: C, 79.62; H. 6.24. Found: C. 79.49; H, 6.64.

Analysis, Calc. for C H O: C, 85.68; H, 7.19. Found: C, 85.44; H. 7.06.

3-Methoxy-4-phenoxy-a-methylstyrene, b.p., 157160/0.07 mm.; n 1.5914, from 2-(3- methoxy-4-phenoxyphenyl)-2-propanol.

Analysis, Calc. for C H O C. 79.97; H. 6.71. Found: C. 79.75; H. 6.76.

4-(4-Fluorophenyl)-a-methylstyrene. m.p., l27128. from 2-(4-fluorobiphenylyl)-2-propanol.

Analysis. Calc. for C H F: C. 84.87; H, 6.17. Found: C. 84.68; H, 6.45.

2-iso-Propenyl-6-methoxynaphthalene, m.p., 93-95, from 2-( 6-methoxy-2-naphthyl )-2-propanol.

Analysis. Calc. for C H O: C. 84.81; H. 7.120. Found: C. 84.61; H. 7.10; 0.

EXAMPLE 27 Preparation of 3-Phenoxy-a-methylstyrene Methyl magnesium iodide was prepared'by the dropwise addition of 228 g. of methyl iodide to a stirred suspension of 36.4 g. of magnesium in 1000 ml. of ether.

A solution of 148 g. of 3- phenoxyacetophenone in 500 ml. of ether was added dropwise. and the reaction mixture was then stirred at room temperature overnight and decomposed by the dropwise addition of 265 m1. of saturated ammonium chloride solution. After water was added, the reaction mixture was extracted with ether and ethyl acetate. The combined organic extracts were washed with water and dried over sodium sulfate. Evaporation of the solvents left an oily residue which was distilled twice to yield 94.8 g. of 3-phenoxy-amethylstyrene, b.p., 103-115/0.08 mm.; n,, 1.5873.

Analysis. Calc. for C, -,H O: C. 85.68; H. 6.71. Found: C. 85.69; H. 6.90.

EXAMPLES 28-29 The following compounds were prepared according to the method of Example 27 using appropriate starting materials.

3-Chloro-4-allyloxy-a-methylstyrene, b.p., 99l05/0.07 mm.-; n 1.5623, from 3-chlor0-4- allyloxyacetophenone.

Analysis. Calc. for H ClO: C. 69.l4; H. 6.29; 0. 7.68. Found: C. 69.23; H. 6.20; 0. 7.85.

4-n-Butyl-a-methylstyrene, b.p., 8488/0.05 mm.; n 1.5182, from 4-n-butylacetophenone.

Analysis. Calc. for C H C. 89.59; H. 10.41. Found: C. 89.48; H. 10.48.

EXAMPLE 30 Preparation of l (4-Cumenyl)cyclooctene A-solution of 4-Cumenyl magnesium bromide was prepared by the dropwise addition of a solution of g. of 4-bromocumene in about 250 ml. of ether to a stirred suspension of 8.75 g. of magnesium turnings in 50 ml. of ether to which a few drops of ethylene bromide had been added, at such a rate that gentle reflux was maintained. The reaction was stirred at room temperature forthree hours. A solution of 38 g. of cyclooctanone in 250 ml. of ether was added dropwise and the Analysis. Calc. for C H C. 89.41; H. 10.59. i v Found: C. 89.46; H. 10.77.-

EXAMPLE 31 Preparation of 2-Hydroxy-2-(4-cumenyl)norbornane 2-Hydroxy-2-(4-cumenyl)norbornane, b.p., 137145/0.1 mm., which contained a trace of 2-(4-cumenyl)-2-norbornene wasprepared in a manner similar to the procedure of Example 30 using appropriate amounts of 4-bromocumene, magnesium, and norcamphor.

EXAMPLE 32 Preparation of 1'(4-Cumenyl)propanol 1-(4-Cumenyl)propanol, b.p., 124-l35/5 mm.; m, 1.5789, was prepared according to the method of Example 31 using appropriate amounts of 4- bromocumene, propionaldehyde, and magnesium.

Analysis. Calc. for C H O: C, 80.85; H. 10.18. Found: C. 81.08; H. 9.92.

EXAMPLE 33,

Preparation of4-Phenylcume'ne A mixture of 21.2 g. of 2-(4-biphenylyl)-2-propanol. 4 g. of 5 percent Pd/C, 20 drops of H SO and 200 ml.

Analysis. Cale. for C I-1 C. 91.78: H. 8.22. Found: C. 92.06; H. 7.97.

EXAMPLES 34-42 The following compounds were prepared according to the method of Example 33 using the corresponding propanol benzyl alcohol, or styrene as the starting material:

4-Phenoxycumene, b.p.. 104110/0.05 mm.; n 1.5591. from 2-(4-phenoxypheny1)-2-propanol.

Analysis. Calc. for C, H O: C. 84.87. H. 7.60. Found: C. 84.80; H. 7.38.

4-Phenylthiocumene, b.p., 135-141/0.07 mm.; r1 1.6000 from 2-(4-phenylthiophenyl)-2-propanol.

Analysis. Calc. for C, H S: C. 78.89; H. 7.06. Found: C. 78.81; H. 7.16.

4-n-Propylcumene, b.p., 8389/5 mm.; n 1.4888. from 1-(4-cumenyl)-1-propano1.

Analysis. Calc. for C H C. 88.82; H. 11.18. Found: C. 88.72; H. 10.91.

4-iso-Butylcumene, b.p., 52-69/0.13 mm.; 11,, 1.9862. from 2-(4-iso-butylphenyl)-2-propanol.

Analysis. Calc. for C H C. 88.56; H. 11.44.

Found: C. 88.85: H. 11.34

4-Cyclopentylcumene. b.p.. 120-130l5 mm.; m, 1.5150. from 4-( l-cyclopentenyl)cumene.

Analysis. Calc. for CuHgo: C. 89.29; H. 10.71. Found: C. 89.06; H. 10.79.

4-Cyclohexy1cumene, b.p.. 105110/0.'1 mm.; n 1.5173. from 2-(4-cyclohexylphenyl)-2-propano1.

Analysis. Calc. for C H C. 89.04; 10.96. Found: C. 89.27; H. 10.66.

12 4-Cyc1ooctylcumene, b.p., 1'26-134/0.1 mm.; m, 1.5230, from 1-(4-cumeny1)cyclooctene.

Analysis. Calc. for C H C. 88.62; H. 11.38. I Found: C. 88.38; H. 11.52.

4-(2-Norbornyl)cumene. b.p.. 150-156l5 mm.; m, 1.5333 from 2-Hydroxy-2-(4-cumenyl)norbornane.

Analysis. Calc. for C H C. 89.65; H. 10.35. Found: C. 89.38; H. 10.20.

4-(4 F1uoropheny1)cumene, m.p., 91-94", from 2- (4-Fluorobiphenyly1)-2-propano1.

Analysis. Calc. for C H F: C 84.08; Found: C. 84.02;

EXAMPLE 43 Preparation of 3-Phenoxycumene A mixture of 21 g. of 3-phenoxy-a-methylstyrene, prepared according to Example 27, l g. of platinum oxide, and 200 ml. of ethanol was hydrogenated until. the calculated amount of hydrogen had been absorbed.

. The catalyst was filtered and the filtrate was evaporated in vacuo. The residual oil was distilled to yield 17.1 g. of 3-phenoxycumene. b.p., 140-150/5 mm.; m, 1.5574.

Analysis. Calc. for C H O: C. 84.87; H. 7.60. Found: C. 84.82; H. 7.51.

I EXAMPLE 44 Preparation of 4-iso-Butyldiphenyl Ether A mixture of 48 g. of 4-phenoxy-iso-butyrophenone.

24 g. of percent hydrazine hydrate. 26.4 g. of 85 percent potassium hydroxide. and 150 ml. of diethylene glycol was stirred and heated to for 1 hour. The reaction mixture was then raised to 200 for 1 hour. to allow volatile materials to distill out of the mixture. The reaction mixture was then allowed to cool somewhat. 20 ml. of water was added. and the reaction mixture was heated at 200 as before for an additional hour. The reaction mixture was cooled and extracted with ether. The ether extract was washed twice with water, dried over sodium sulfate, and evaporated in vacuo. The residual oil was distilled twice to yield 29.2 g. of 4-iso-butyldiphenyl ether. b.p., 121-130/0.1 mm.; 11,, 1.5461.

Analysis. Calc. for C H O: C. 84.91. H. 8.02. Found: C. 84.95. H. 7.97.

EXAMPLE 45 Preparation of 4-neo-pentylcumene 4-neo-Pentylcumene, b.p., 65.68/0.7 mm.; 11,,

1.4857, was prepared according to the method of Example 44 from 4-cumenyl-tert-butyl ketone.

Analysis, Calc'. for c,,H,,; c. 88.3.5; H, 11.65. Found: c. 88.13; H. 11 4;.

In the practice of this invention, one of the antiinflammatory agents'disclosed herein is administered to a subject suffering from an inflammatory condition in dosages of from about1.0 to about 100 mg./kg. of body weight daily, either in single or divided doses. If divided doses are utilized, the anti-inflammatory agent is generally administered every 4'to 6 hours. Since some of the I dosage depends upon the desired therapeutic effect, on

the route of-administration, and on the duration of the treatment. Generally, dosage levels of between 1.0 to

i 100 mg./kg. of body weight daily are administered to anti-inflammatory agents used in the-practice of this intice of this invention are oils, they may first be adsorbed onto an inert carrier such as talc, silica gel, or

the like before they are formulated into capsules, tab- .lets, pills, powders, or granules. Such. solid dosage forms'for oral administration can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. These compounds can also be incorporated into soft gelatin capsules.

Liquid dosage forms for oral administration include such pharmaceutically acceptable forms as emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or a suitable oil.

In formulating the compounds ofthis invention in liquid dosage forms fororal administration, it may be preferred to dilute the agent to be formulated with a suitable oil such as peanut oil, cottonseed oil, sesame oil, or corn oil or the like. Such diluted mixture comprises the internal phase of the emulsion. Flavoring agents, sweetening agents and the like are dissolved in water which acts as the external phase of the emulsion. Besides inert diluents, such compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Compositions for rectal administration or suppositories which may contain in addition to the active sub stances, excipient; such as cacao butter or a suppository wax.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected mammals to obtain effective relief of inflammation, pain, and with some compounds, fever. However, prescribed doses of one or more of these compounds in a suitable formulation will probably range from about 50 mg. to 1000 mg. l to 4 times a day depending upon the .patient body weight, the condition being treated, and other factors of concern to the patients physician.

EXAMPLE 46 Capsule Formulation 4 Phenylcumene I 0% Silica Gel (Syloid 2441 The 4-phenylcumene is mixed with silica gel ina suit-' able mixer to produce .a homogeneous powder. The powder may be packed into suitable size empty gelatin capsules for administration of the drug. Typically, a No. 00 gelatin capsule has been found to hold 055 g. powder, equivalent to 330 mg. drug. Other-ingredients may be added according to the art for the purpose of improving performance of processing machines, assist ing in disintegration of the unit dose, improvement of compactability, etc.

Other materials, of which silica gel is only one example, may be used, either singly or in combination, to adsorb and convert the compounds of subject patent which are oily in nature, to a dry powder.

EXAMPLE 47 Soft Elastic'Capsule Formulation 4-Phenylcumene may be encapsulated in a soft gela- I EXAMPLE'48 Emulsion Formulation 4-Phenylcumene 1.33 g. Soybean Oil 26.7 g. Span 60 2.27 g. Tween 60 0.40 g. Sucrose 33.3 g. Methylparaben 0.1 g. Propylparaben 0.1 g. Peppermint Oil 0.05 g. Water q.s. 100 ml. Dose: 15 ml.. equivalent to 200 mg. drug The Span 60 and soybean oil are mixed and heated to C. Tween 60 and parabens are dispersed in approximately ml. water at 70C. and sucrose is added. The oil phase is added to the aqueous phase in a suitable mixer such as a Waring Blender and mixed to produce a milky product. After cooling, the 4- phenylcumene and. peppermint oil are added, and the mixture is agitated again.

EXAMPLE 49 Suppository Formulation 4Phenylcumene 15.5% by wt. White Wax. USP 4.0% Theobroma Oil. USP 80.5%

White wax is dissolved in the 4-phe'nylcumene with the aid of gently heat. Theob'roma oil is shaved and added to the mixture slowly. After the theobroma oil has been completely melted, with the aid of additional heat as required, the mixture may be poured into suppository molds of suitable size for the desired dose; e.g., a 2.58 g. suppository of the above mixture yields a 400 mg. dose of 4-phenylcumene.

EXAMPLE 50 Tablet Formulation 4Phenylcumene Silica Gel Avicel Starch Flowable Stearie Acid 4-Phenylcumene is mixed with silica gel to produce a dry powder which may be blended with the remaining ingredients, previously blended. The formulation may then be compressed by a suitable tablet machine to produce tablets of desired weight, typically 667 mg. equivalent to 100 mg. 4-phenylcumene.

Footnotes Span 60 is sorbitan monostearate Atlas Chemical Industries Inc.

Tween 60 is polyoxyalkylene derivative of sorbitan monostearate City Chemical Corp. N.Y., N.Y.

Avicel is microcrystalline form of cellulose American Viscose Corp., Merck Index, Eighth edition, page 220.

EXAMPLE 5i Anti-Inflammatory Effect of 4-Phenylcumene On Ultraviolet-Induced Erythema in Guinea Pigs The effects of various formulations of 4- phenylcumene were evaluated on the development of ultraviolet-induced erythema on albino guinea pig skin. The formulations were administered orally; rectally and subcutaneously.

Methods A modification of the Winder et al. (1958) method was used to measure the anti-inflammatory activity of this agent. Albino guinea pigs of either sex weighing 225-300 grams were shaved on the back and chemically (Nair, Lotion Hair Remover, Carter Products, N.Y., N.Y.) depilatated 18-20 hours before exposure to ultraviolet light. The animals were fasted overnight. Immediately after the guinea pigs were treated with a test compound, a gummed notebook paper reinforcement was placed on their backs and they were exposed to a high intensity ultraviolet light for 7 seconds. The ultraviolet light source was a Hanovia Lamp (Kromayer-Model 10) which was placed in contact with the skin of the guinea pig's back. After exposure, the reinforcements were removed and the back wiped clean with a water soaked gauze sponge. The unexposed area under the reinforcement provided an area of contrast for grading the erythema. The animals were randomized and placed in clear plastic partitioned holders l0 X 20 cm. wide and 15 cm. high. Beginning one hour after exposure and thereafter at half-hour intervals for another I /2 hours, the degree of resulting erythema was graded by an arbitrary scoring system based upon the degree of contrast and redness formed. Antiinflammatory agents delay the development of the erythema and therefore have their greatest effect at the initial grading periods. Therefore, the scores were weighed by a factor of 4, 3, 2, and l at the 1.0, 152.0, and 2.5 hour scoring times respectively. The erythema was graded as follows:

Erythema Scoring System Score Appearance of Exposed Area 0 No redness and no contrast I Slight redness with a faint reinforcement outline 2 Slight to moderate redness with a distinct outline 3 Marked redness with a distinct circular outline Total scores from each treatment group of four guinea pigs were compared to the control treatment and the percent inhibition calculated as follows:

X (Control Treatment)/(Control) Inhibition The formulations of Compound 65268 tested were as follows:

50% inhibition of the erythemic response (ED in the methyl cellulose suspension was determined to be 4.0 mg./kg. The response to subcutaneous administration of this formulation was not greatly different.

The compound, when adsorbed on Silica Gel (Syloid 244) and administered in a water suspension at a dose of 50 mg./kg. orally, produced a 92% inhibition of the erythemic response.

Emulsion: When administered orally at a dose of approximately 38 mg./kg., the emulsion produced a 79% inhibition of the erythemic response.

The theobroma oil suppositories administered rectally at an approximate dose of 35 mg./kg. produced a 50% inhibition of the erythemic response.

CONCLUSIONS 4-Phenylcumene was found to be effective in inhibiting the erythemic response to ultraviolet-induced erythema in guinea pigs in all of the formulations tested.

REFERENCES Winder, C.V.; Wax, 1.; Burr, V.; Been, M.; and Posiere, C.E.: A Study of Pharmacological Influences on Ar-R wherein Ar represents an aryl moiety selected from the group consistingv of 3-phenoxyphenyl, 4-phenoxyphenyl, 4-phenoxy-3-methylphenyl,' 4-phenoxy-3- methoxyphenyl, 6-methoxy-2-naphthyl, or 3-chloro-4-allyloxyphenyl; and

R represents iso-propyl, iso-propenyl, or iso-butylf with the limitation that when R is iso-butyl, Ar is 4-phenoxyphenyl. 2. The method of claim 1 wherein the compound is 3-phenoxy-a-methylstyrene.

3. The method of claim 1 wherein 3-phenoxycumene.

4. The method of claim l'wherein the compound is 4-phenoxy-a-methylstyrene.

the compound is 5. The method of claim I wherein the compound is 4phenoxycumcne.

6. The method of claim 1 wherein the compound is 3-methyl-4-phenoxy-a-methylstyrene.

7. The method of claim 1 wherein the compound is 3-methoxy-4-phenoxycumene.

8. The method of claim Iwherein the compound is 3 -methoxy-4-phenoxy-a'methylstyrene.

9. The method of claim 1 wherein the compound is 4-iso-butyldiphenyl ether.

0- Thcmeth dd 1aim. ..w n h maq n is 2-iso-propenyl-6-methoxynaphthalene.

11. The method of claim 1 wherein the compound is 3-chloro-4-allyloxy-a-methylstyrene.

12. A pharmaceutical preparation in dosage unit 3 form adapted for administration to obtain an antiinflammatory effect, comprising'per dosage unit, an anti-inflammatory effective nontoxic amount within the range from about 50 to about 500 milligrams of at least one compound defined in claim 1, and a pharmaceutical diluent. g

13'. A pharmaceutical preparation in accordance with claim '12 in a form adapted for oral administration. 

1. THE METHOD OF TREATING INFLAMMATORY CONDITIONS IN MAMMALS WHICH COMPRISES ADMINISTERING TO A MAMMALIAN SUBJECT FROM 1 TO 100 MG./KG. DIALY OF A COMPOUND OF THE FORMULA
 2. The method of claim 1 wherein the compound is 3-phenoxy-Alpha -methylstyrene.
 3. The method of claim 1 wherein the compound is 3-phenoxycumene.
 4. The method of claim 1 wherein the compound is 4-phenoxy-Alpha -methylstyrene.
 5. The method of claim 1 wherein the compound is 4-phenoxycumene.
 6. The method of claim 1 wherein the compound is 3-methyl-4-phenoxy- Alpha -methylstyrene.
 7. The method of claim 1 wherein the compound is 3-methoxy-4-phenoxycumene.
 8. The method of claim 1 wherein the compound is 3-methoxy-4-phenoxy- Alpha -methylstyrene.
 9. The method of claim 1 wherein the compound is 4-iso-butyldiphenyl ether.
 10. The method of Claim 1 wherein the compound is 2-iso-propenyl-6-methoxynaphthalene.
 11. The method of claim 1 wherein the compound is 3-chloro-4-allyloxy- Alpha -methylstyrene.
 12. A pharmaceutical preparation in dosage unit form adapted for administration to obtain an anti-inflammatory effect, comprising per dosage unit, an anti-inflammatory effective nontoxic amount within the range from about 50 to about 500 milligrams of at least one compound defined in claim 1, and a pharmaceutical diluent.
 13. A pharmaceutical preparation in accordance with claim 12 in a form adapted for oral administration. 